T-cells represent the most potent effector arm for the rejection of cancer in response to immunostimulation. In order to understand and augment this effector function, it is necessary to develop methods for generating tumor-reactive T-cells and then augment these pathways through the manipulation of normal immune response pathways. Dendritic cells (DC) represent the master antigen presenting cell and their biology is being rapidly elucidated. Ways to exploit this information and to use them to present whole tumor cells would result in T-cell responses with the greatest potency and breadth. We are currently using renal cancer as a model (wherein tumor is readily available and immunotherapy is known to be effective in some patients) to explore the efficient generation of tumor-reactive T-cells using DC and tumor cells as the stimulus. Preliminary work has shown this to be a very fruitful avenue in that 9 of 9 patients thus far studied using autologous DC, autologous tumor and autologous PBMC have produced tumor-reactive T-cells suitable for antigen discovery and possibly future adoptive cell therapy. The use of tumor apoptotic bodies as the source of antigen has been most effective and this has produced both CD4 and CD8-restricted T-cells in most patients. Future studies are focusing on using this methodology to investigate the full repertoire of immune cells that can recognize renal cancer. Additional patients are being studied with this method and we are applying selection techniques for enriching for tumor-reactivity. Capture techniques exploiting markers of recognition such as CD107a are being explored. We have shown that such markers not only identify classic T-cells, but also lytic NK-T-like populations with excellent reactivity with RCC. This project also continues to be a source of reagents for ongoing antigen cloning projects.